ISOLATION AND STRUCTURE OF A COVALENT CROSS-LINK ADDUCT BETWEEN MITOMYCIN-C AND DNA
ISOLATION AND STRUCTURE OF A COVALENT CROSS-LINK ADDUCT BETWEEN MITOMYCIN-C AND DNA
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DOI：
10.1126/science.3103215
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发表时间：
1987-03-06
期刊：
影响因子：
56.9
通讯作者：
NAKANISHI, K
中科院分区：
文献类型：
--
作者：
TOMASZ, M;LIPMAN, R;NAKANISHI, K
抗肿瘤剂丝裂霉素 C (MC) 与 DNA 的 DNA 交联加合物已被分离和表征；该结果为MC对DNA进行双功能烷基化提供了直接证据。在还原条件下将 MC 暴露于藤黄微球菌 DNA，随后进行核酸酶消化，在 MC 和脱氧鸟苷残基之间形成加合物。除了两种已知的单加合物之外，还获得了双加合物。用 Na2SO4（连二亚硫酸钠）进行还原性 MC 活化会导致独特的双功能烷基化。双加合物的结构通过光谱方法测定，包括质子磁共振、微分傅里叶变换红外光谱和圆二色性。向大鼠注射 MC 后，证实了体内相同双加合物的形成。计算机生成的双加合物模型被纳入 d(CGTACGTACG)2 双链体 B-DNA 十聚体中心，表明双加合物紧密贴合到小沟中，DNA 结构的扭曲最小。对控制单官能和双官能加合物形成的因素进行了机械分析。
A DNA cross-link adduct of the antitumor agent mitomycin C (MC) to DNA has been isolated and characterized; the results provide direct proof for bifunctional alkylation of DNA by MC. Exposure of MC to Micrococcus luteus DNA under reductive conditions and subsequent nuclease digestion yielded adducts formed between MC and deoxyguanosine residues. In addition to the two known monoadducts, a bisadduct was obtained. Reductive MC activation with Na2SO4 (sodium dithionite) leads to exclusive bifunctional alkylation. The structure of the bisadduct was determined by spectroscopic methods that included proton magnetic resonance, differential Fourier transform infrared spectroscopy, and circular dichroism. Formation of the same bisadduct in vivo was demonstrated upon injection of rats with MC. Computer-generated models of the bisadduct that was incorporated into the center of the duplex B-DNA decamer of d(CGTACGTACG)2 indicated that the bisadduct fit snugly into the minor groove with minimal distortion of DNA structure. A mechanistic analysis of the factors that govern monofunctional and bifunctional adduct formation is presented.